Renin is a natural enzyme which is released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing decapeptide, angiotensin I. This is in turn cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renins have been sought as an agent for control of hypertension, congestive heart failure, and hyperaldosteronism.
The present invention concerns novel peptides which inhibit renin. It also concerns pharmaceutical compositions containing these novel peptides, methods of treating renin-associated hypertension, congestive heart failure, and hyperaldosteronism, as well as the use of the peptides as diagnostic tools, and the methods for preparing the peptides.
U.S. Pat. No. 4,479,941 covers certain renin-inhibitory peptides of the formula ##STR1## European Application No. 85/308759 covers certain renin-inhibitory dipeptides of the formula ##STR2## wherein m is 0 or 1 and R.sup.1 -R.sup.5 are a variety of organic groups.
European Application No. 184,855 covers renininhibitory peptides of the formula ##STR3## wherein A is an N-protecting group; R.sub.1, R.sub.3, R.sub.5 and R.sub.7 are lower alkyl or lipophilic or aromatic amino acid side chains and may be the same or different; R.sub.2, R.sub.4 and R.sub.6 are hydrogen or lower alkyl and may be the same or different; X is hydrogen, lower alkyl or --CH.sub.2 --OR.sub.8, wherein R.sub.8 is hydrogen, lower alkyl or alkaryl; and R.sub.9 is lower alkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, alkaryloxy or thioalkyl and pharmaceutically acceptable salts thereof.
European Application No. 192,544 covers peptide pepstatin analogues of the formula ##STR4## wherein R.sub.1 is COR or SO.sub.2 R.sup.1 ; R.sub.2 is optionally substituted lower alkyl, phenyl, naphthyl, cyclohexyl or pyridyl; R.sub.3 is hydrogen, lower alkenyl, phenyl, naphthyl, 3-6C cycloalkyl, monocyclic heterocyclic or substituted lower alkyl; Z.sub.1 is i-Pr, phenyl, cyclohexyl; X-Y is a dipeptide.
European Application No. 220,665 covers peptidyl; amino cycloalkyl; hydroxy alkanoic acid derivatives of the formula EQU X--Z--NR.sub.2 --CHR.sub.3 --CHOH--(CHR.sub.4).sub.n --CO--E
wherein
X=H,R.sub.1 OC.sub.m H.sub.2m CO, R.sub.1 C.sub.m H.sub.2m OCO, R.sub.1 C.sub.m H.sub.2m CO, R.sub.1 SO.sub.2, Q-C.sub.r H.sub.2r CO, H(NHCH.sub.2 CH.sub.2).sub.m NHCH.sub.2 CO or 9-fluorenyl-C.sub.m H.sub.2m OCO; PA0 Z=1-4 peptide-linked aminoacid gps. selected from Abu, Ada, Ala, Arg, Asn, Bia, Cal, Dab, Gln, Gly, His, N(im)-alkyl-His, Ile, Leu, tert-Leu, Lys, Met, .alpha.-Nal, .beta.-Nal, Nbg, Nle, Orn, Phe, Pro, Ser, Thr, Tic, Trp, Tyr and Val; and PA0 E=OH, OA, NH.sub.2, NHA or N(A).sub.2.
The compounds are useful as renin and acid protease inhibitors.
Since HIV protease, like renin, is an aspartyl protease, these compounds can also be used to treat diseases caused by retroviruses including HTLV-I and -III.